The underlying theme of the research program is a study of mechanisms which might alter the inheritance of somatic cells and hence could result in quantitative or qualitative abnormalities in proteins and thus produce disease. This somatic cell genetics approach to cellular pathology will be focused upon two major and interrelated problems: 1) the mapping of the human genome and 2) the genetic control of cell senescence. The principal research materials will be established lines of skin fibroblasts and peripheral blood lymphoid cells. One of the latter non-senescing and normal diploid cell lines will be extensively investigated as a standard or "wild-type" cell line from which various mutant clones will be derived in-vitro. Among those mutations which are expressed in cell cultures from individual human donors, special attention will be devoted to the mutations responsible for Werner's syndrome and progeria, in an effort to elucidate the underlying biochemical defects.